PLoS Genetics最新文献

{"title":"Dynamics of recombination, X inactivation and centromere proteins during stick insect spermatogenesis.","authors":"Zoé Dumas, William Toubiana, Marie Delattre, Tanja Schwander","doi":"10.1371/journal.pgen.1011827","DOIUrl":"10.1371/journal.pgen.1011827","url":null,"abstract":"<p><p>In eukaryotes, the cellular processes contributing to gamete formation form the building blocks of genetic inheritance across generations. While traditionally viewed as conserved across model organisms, emerging studies reveal significant variation in meiotic and post-meiotic processes. Extending our knowledge to non-model organisms is therefore critical to improve our understanding of the evolutionary origin and significance of modifications associated with gamete formation. We describe the cytological patterns underlying chromosome segregation, recombination, and meiotic sex chromosome inactivation during male meiosis in the stick insect group Timema. Our results provide a detailed description of centromere protein loading dynamics during spermatogenesis, and further reveal that 1) recombination initiates before synapsis (unlike Drosophila meiosis), and 2) that the X remains actively silenced despite two waves of transcriptional activation in autosomes during spermatogenesis. Together, our observations help understand the evolutionary significance of key cellular events related to spermatogenesis and shed light on the diversity of their associated molecular processes among species, including Timema stick insects.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011827"},"PeriodicalIF":3.7,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12393702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144876383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The highly dynamic pangenome of basal chordates is enriched in defence and immunity genes and is inherited following the Mendelian law.","authors":"Umberto Rosani, Marco Gerdol, Mart Krupovic","doi":"10.1371/journal.pgen.1011833","DOIUrl":"10.1371/journal.pgen.1011833","url":null,"abstract":"<p><p>Pangenome analyses, which encompass the full genetic repertoire of a species, offer valuable insights into intraspecific diversity and phylogeographic gene patterns. While the taxonomic breadth and functional significance of animal pangenomes remain to be fully uncovered, recent findings (such as reports of open, bacterial-like pangenomes in bivalves) highlight the need to better understand the molecular mechanisms driving inter-haplotype structural variation. Genes affected by presence-absence variation (PAV), along with non-reference sequences (NRSs), represent evolutionary footprints that may shape genome architecture and plasticity, ultimately influencing the adaptability and long-term fitness of species. To investigate the pangenomic architecture of basal chordates, we analyzed available whole-genome resequencing data from Branchiostoma belcheri and B. floridae, examined the impact of structural genomic variation, and assessed the inheritance patterns of dispensable genes across generations. The pangenomes of both species include over a thousand of genes affected by PAV and exhibiting trans-generational Mendelian transmission from parents to offspring. We further demonstrate that 35 dispensable genes in B. belcheri are of exogenous origin, likely resulting from the integration of a malacoherpesvirus genome, thereby extending the known host range of Malacoherpesviridae from invertebrates to chordates. PAV preferentially targeted gene families involved in defense, immunity, and cell signaling, including GTPases of immunity-associated proteins (GIMAPs), caspases, toll-like receptors, and pattern recognition receptors containing apextrin C-terminal (APEC) domains. The dynamic nature of immunity genes in cephalochordates parallels patterns seen in open bacterial pangenomes, suggesting that fundamental principles of genome evolution and innovation across life domains are shaped by host-pathogen interactions.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011833"},"PeriodicalIF":3.7,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144876397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two pairs of CACNA1I (CaV3.3) variants with opposite effects on channel function cause neurodevelopmental disorders of varying severity.","authors":"Yousra El Ghaleb, Monica L Fernández-Quintero, Marta Campiglio, Petronel Tuluc, Ann-Sophie Höing, Fanny Kortüm, Mahdi M Motazacker, Iris E Jansen, Mariet W Elting, Astrid S Plomp, Anna-Lena M Fischer, Victoria M Siu, Kerstin Kutsche, Bernhard E Flucher","doi":"10.1371/journal.pgen.1011828","DOIUrl":"10.1371/journal.pgen.1011828","url":null,"abstract":"<p><p>The T-type voltage-gated calcium channel CaV3.3 is expressed in GABAergic neurons of the thalamic reticular nucleus (TRN), where its pacemaking activity controls sleep spindle rhythmogenesis during the non-rapid eye movement (NREM) phase of natural sleep. Previously, we established CACNA1I, the gene coding for CaV3.3, as a disease gene for neurodevelopmental disease with or without epilepsy. Here we report three newly identified activation-gate-modifying heterozygous missense variants of CACNA1I, found in four unrelated patients with neurodevelopmental disease with or without seizures. One of these variants, p.(Met1425Val), is an amino-acid substitution at the same position as previously published variant p.(Met1425Ile). Notably, the other two variants studied here are also a pair of two different substitutions of the same amino acid: p.(Ala398Val) and p.(Ala398Glu). By using site-directed mutagenesis, voltage-clamp electrophysiology, computational modelling of neuronal excitability, and structure modelling, we found that the two substitutions of M1425 both result in a gain of channel function including left-shifted voltage-dependence of activation and inactivation, slowed inactivation and deactivation kinetics, and increased neuronal excitability. Remarkably, the two substitutions of A398 show opposite effects on channel function. While substitution A398E leads to a gain of channel function, A398V results in decreased current density, accelerated gating kinetics, and a decreased neuronal excitability. The lack of seizures in the two independent p.(Ala398Val) patients correlates with the absence of increased neuronal excitability in this variant. This is the first report of a gate-modifying CaV3.3 channel variant with partial loss-of-function effects associated with developmental delay and intellectual disability without seizures. Our study corroborates the role of CaV3.3 dysfunction in the etiology of neurodevelopmental disorders. Moreover, our data suggest that substantial gain-of-function of CaV3.3 leads to the development of seizures, whereas both gain- and loss-of-function variants of CACNA1I can cause neurodevelopmental disease.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011828"},"PeriodicalIF":3.7,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12396757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144876398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding the alcohol harm paradox: A multivariable mendelian randomization approach.","authors":"Gemma Sawyer, Hannah Sallis, Marcus Munafò, Liam Mahedy, Jasmine Khouja","doi":"10.1371/journal.pgen.1011824","DOIUrl":"10.1371/journal.pgen.1011824","url":null,"abstract":"<p><p>The alcohol harm paradox, whereby low socioeconomic position (SEP) groups experience greater alcohol-related harms at a given level of alcohol consumption, is not yet fully understood. In observational studies, key drivers are correlated and share similar confounding structures. We used multivariable Mendelian randomization (MVMR) to estimate the direct causal effect of alcohol (drinks per week) and education (years of schooling) on multiple health outcomes, accounting for the effect of the other. Previously published genome-wide association summary (GWAS) statistics for drinks per week and years of schooling were used, and outcome summary statistics were generated from individual-level data from UK Biobank (N = 462,818). Inverse variance weighted analyses demonstrated evidence for direct effects of alcohol and education on liver diseases (alcoholic liver disease: alcohol OR = 50.19, 95% CI 19.35 to 130.21 and education OR = 0.27, 95% CI 0.14 to 0.53; other liver diseases: alcohol OR = 1.82, 95% CI 1.12 to 2.94 and education OR = 0.42, 95% CI 0.30 to 0.58), mental and behavioural disorders due to alcohol (alcohol OR = 12.89, 95% CI 7.46 to 22.27 and education OR = 0.51, 95% CI 0.35 to 0.75), and stroke (alcohol OR = 1.94, 95% CI 1.30 to 2.89 and education OR = 0.73, 95% CI 0.55 to 0.97). There was evidence for direct effects of education on depression, anxiety, influenza/pneumonia, and heart disease. In contrast, there was evidence of total (without considering the effect of education), but not direct, effects of alcohol on depression, influenza/pneumonia, epilepsy, and injuries. Although caution is required when interpreting these results, given weak instruments for alcohol, these results provide some evidence that the alcohol harm paradox is partially due to the protective effect of additional years of education. Replication with strong genetic instruments for drinks per week would be necessary to draw causal inferences.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011824"},"PeriodicalIF":3.7,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12370186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144856854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Defining transcription factor nucleosome binding with Pioneer-seq.","authors":"Maria Tsompana, Patrick D Wilson, Vijaya Murugaiyan, Christopher R Handelmann, Michael J Buck","doi":"10.1371/journal.pgen.1011813","DOIUrl":"10.1371/journal.pgen.1011813","url":null,"abstract":"<p><p>Gene expression requires the targeting of transcription factors (TFs) to regulatory sequences often occluded within nucleosomes. To comprehensively examine TF nucleosome binding, we developed Pioneer-Seq. In Pioneer-seq a library of thousands of nucleosomes are formed from sequences containing a TF binding site (TFBS) variant in all possible nucleosome orientations and within the linker regions. Pioneer-seq has the unique ability to simultaneously examine nucleosomes created with various nucleosome positioning sequences and examine binding to in vivo targeted nucleosomes (ITNs). Pioneer-seq can be applied to address various mechanistic models for TF-nucleosome binding directly and can be used to uncover inherent TF-interaction differences. To demonstrate Pioneer-seq, we examined nucleosome binding by OCT4, SOX2, KLF4, and c-MYC. Our results demonstrate that all studied TFs can bind at nucleosome edges and nucleosome sequence is the primary factor regulating TF binding. In addition, KLF4 can bind to a non-canonical TFBS located 20 bp from the nucleosome dyad. Examination of ITNs showed binding differences between the TFs, with KLF4 and SOX2 binding more often near nucleosome centers. Overall, our results demonstrate differences in how TF recognizes their TFBS within a nucleosome and begins to define the mechanistic requirements for pioneer factor binding.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011813"},"PeriodicalIF":3.7,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12370185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144856853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Pcdh15 in the development of intrinsic polarity of inner ear hair cells.","authors":"Raman Kaushik, Shivangi Pandey, Anubhav Prakash, Fenil Ganatra, Takaya Abe, Hiroshi Kiyonari, Raj K Ladher","doi":"10.1371/journal.pgen.1011825","DOIUrl":"10.1371/journal.pgen.1011825","url":null,"abstract":"<p><p>In vertebrates, auditory information is transduced in the cochlea by mechanosensory hair cells (HC) through an eccentrically organised structure known as the hair bundle. This consists of a true cilium, known as the kinocilium, and modified microvilli, known as stereocilia. The hair bundle has a distinct structure with stereocilia organised in graded rows, with the longest abutting the kinocilium. The hair bundles of all HC are aligned to the tissue axis and are planar polarised. Important in the development and physiology of HC are protein bridges consisting of cadherin-23 (CDH23) and protocadherin-15 (PCDH15). These link the tips of stereocilia, where they play a role in mechanotransduction, and between the kinocilia and the stereocilia, where they are involved in development. Both Cdh23 and Pcdh15 mutations result in defects in planar polarity; however, the mechanism through which this defect arises is unclear. Using a novel mutant for the Pcdh15-CD2 isoform, we show that while the initial deflection of the kinocilium occurs, its peripheral migration to register with Gαi is perturbed. Pcdh15-CD2 genetically interacts with Gpsm2, perturbing vestibular function. We find that the earliest expression of PCDH15-CD2 is at the base of the kinocilia, and the defects in morphogenesis occur before the formation of kinocilial links. By re-introducing functional PCDH15-CD2, we show that polarity can be restored. Our data suggest that, in addition to its adhesive role, PCDH15-CD2 has an early role in intrinsic hair cell polarity through a mechanism independent of kinocilial links.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011825"},"PeriodicalIF":3.7,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12370195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144849431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polymerization and flanking domains of the bactofilin BacA collectively regulate stalk formation in Asticcacaulis biprosthecum.","authors":"Maxime Jacq, Paul D Caccamo, Yves V Brun","doi":"10.1371/journal.pgen.1011542","DOIUrl":"10.1371/journal.pgen.1011542","url":null,"abstract":"<p><p>Bactofilins are a recently discovered class of cytoskeletal protein, widely implicated in subcellular organization and morphogenesis in bacteria and archaea. Several lines of evidence suggest that bactofilins polymerize into filaments using a central β-helical core domain, flanked by variable N- and C- terminal domains that may be important for scaffolding and other functions. In Asticcacaulis biprosthecum, the bactofilin BacA serves as a topological organizer of stalk synthesis, localizing to the stalk base and coordinating the synthesis of these long, thin extensions of the cell envelope. The easily distinguishable phenotypes of wild-type A. biprosthecum stalks and ΔbacA \"pseudostalks\" make this an ideal system for investigating how mutations in BacA affect its functions in morphogenesis. Here, we redefine the core domain of A. biprosthecum BacA using various bioinformatics and biochemical approaches to precisely delimit the N- and C- terminal domains. We then show that loss of these terminal domains leads to cells with severe morphological abnormalities, typically presenting a pseudostalk phenotype. BacA mutants lacking the N- and C- terminal domains also exhibit localization defects, implying that the terminal domains of BacA may be involved in its subcellular positioning, possibly through regulatory interactions with membrane-associated factors or other morphological proteins. We further show that point mutations that render BacA defective for polymerization lead to stalk synthesis defects. Overall, our study suggests that BacA's polymerization capacity and domain-mediated cellular positioning play a crucial role in the protein's function as a morphogenic regulator.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011542"},"PeriodicalIF":3.7,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12364344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144849430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An l-fucose-responsive transcription factor cross-regulates the expression of a diverse array of carbohydrate-active enzymes in Trichoderma reesei.","authors":"Qinqin Zhao, Liwei Gao, Nuo Xu, Xiuting Zhang, Yuqi Qin, Yinbo Qu, Guodong Liu","doi":"10.1371/journal.pgen.1011815","DOIUrl":"10.1371/journal.pgen.1011815","url":null,"abstract":"<p><p>l-Fucose is a universal capping component of biomolecules found throughout all domains of life. Although fungi are renowned for their role in biomass recycling, the mechanisms by which they process l-fucose remain largely unknown. In this study, we elucidate a l-fucose-responsive system in Trichoderma reesei, a model fungus for plant cell wall degradation. Central to this system is the transcription factor FUR1, which is indispensable for growth on l-fucose. FUR1 orchestrates the expression of l-fucose catabolic enzymes, including an l-fucose dehydrogenase that exhibits distant homology to counterparts in bacteria and mammals. Through RNA sequencing and biochemical assays, we demonstrate that FUR1 also governs the enzymatic liberation of l-fucose by upregulating extracellular α-l-fucosidases. Intriguingly, FUR1 mediates l-fucose-triggered expression of a broad spectrum of enzymes that target diverse glycosidic bonds (e.g., β-glucuronidic, α-galactosidic, and β-xylosidic linkages) within complex carbohydrates. Expression of a constitutively active FUR1 mutant unlocked the production of otherwise silent glycosidases, substantially boosting the hydrolytic capacity of the fungal secretome on orange peel. These findings offer the first molecular insight into l-fucose sensing and metabolism in fungi, and advance our understanding of the fungal regulatory network for coordinated expression of biomass-degrading enzymes.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011815"},"PeriodicalIF":3.7,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12370193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144822984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Threshold-dependent negative autoregulation of PIF4 gene expression optimizes growth and fitness in Arabidopsis.","authors":"Sreya Das, Vikas Garhwal, Krishanu Mondal, Dipjyoti Das, Sreeramaiah N Gangappa","doi":"10.1371/journal.pgen.1011758","DOIUrl":"10.1371/journal.pgen.1011758","url":null,"abstract":"<p><p>PHYTOCHROME INTERACTING FACTOR 4 (PIF4) is a vital transcription factor that controls plant growth by integrating environmental signals like light and temperature. Recent studies have shown many upstream regulators, such as HEMERA (HMR), HEAT SHOCK TRANSCRIPTION FACTORS (HSFs), TEOSINTE BRANCHED 1/CYCLOIDEA/PCF 5 (TCP5), and the B-BOX (BBX) proteins, play roles in regulating PIF4 transcription. However, the role of PIF4 in controlling its own gene expression is unknown. Here, we demonstrate that the PIF4 undergoes negative autoregulation. We show that PIF4 promoter activity is higher in the pif4 mutant but significantly reduced in PIF4 overexpression transgenic lines. Moreover, CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1) enhances PIF4 protein stability and promotes PIF4 autoinhibition. However, Phytochrome B (phyB), a photoreceptor that decreases PIF4 stability, inhibits autoinhibition. We further develop a network-based mathematical model incorporating the PIF4 autoinhibition and other key interactions. Our modeling and data analysis reveal that PIF4 autoregulation depends on a threshold of cellular PIF4 concentration. Our model also successfully predicts the hypocotyl growth and PIF4 promoter activity in various light and temperature conditions. Moreover, we show that the transgenic lines with enhanced PIF4 function negatively influence biomass and yield, irrespective of photoperiod and temperature. Together, the negative feedback of PIF4 dampens its own function and restrains unregulated growth. Our study thus elucidates the mechanisms of how the phyB-COP1/DET1-PIF4 module controls PIF4 transcription in tune with the endogenous PIF4 level.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011758"},"PeriodicalIF":3.7,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12338842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144823049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene dosage and protein valency impact phase separation and fungal cell fate.","authors":"Collin Ganser, Peiling He, Corey Frazer, Damian J Krysan, Richard J Bennett","doi":"10.1371/journal.pgen.1011810","DOIUrl":"10.1371/journal.pgen.1011810","url":null,"abstract":"<p><p>Cell fate decisions in eukaryotes are regulated by interconnected networks of transcription factors (TFs) that drive heritable changes in identity. However, much is unknown about how TFs act together to control cell fate, despite links to cellular dysfunction and disease when TF function is aberrant. Here, we addressed the interplay between TFs that control heritable switching in the diploid fungal pathogen Candida albicans. This species can propagate in two distinct cell states, white and opaque, with epigenetic transitions between states regulated by a core network of eight TFs plus >100 auxiliary TFs. The role of these TFs was dissected using simple and complex haploinsufficiency (CHI) analyses to examine the impact of gene dosage on cell fate. Among single heterozygotes, loss of one allele of WOR1 had the greatest impact on white-opaque switching, consistent with its role as the master opaque regulator, while CHI analysis revealed strong genetic interactions between other core TFs including WOR3 and WOR4. Wor1 function was also highly sensitive to its interaction valency, a measure of the number of inter-molecular interactions it can undergo. Engineered strains with increased Wor1 valency, either via the addition of extra prion-like domains (PrLDs) or by forced dimerization, increased switching frequencies by up to two orders of magnitude. Increasing Wor1 valency increased its propensity to form phase-separated condensates both in vitro and in mammalian cells. Together, these experiments establish that changes to TF gene dosage and TF valency can alter cell fate determination, with these changes linked to the propensity of TFs to undergo condensate formation.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011810"},"PeriodicalIF":3.7,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12333994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}